Although the term chronic traumatic encephalopathy (CTE) has only recently entered the research and common vernacular, the neuropsychiatric sequelae have been recognized for decades as dementia pugilistica (DP) in some individuals with careers in boxing. Yet, despite the intense new interest in `CTE', the number of reported cases has been surprisingly limited and there are no validated neuropathological diagnostic criteria to define it as a distinct disease entity. Notwithstanding this, there is a widely held, abeit unfounded, perception that repetitive TBI (rTBI) alone culminates in `CTE' and that `CTE' is primarily characterized by a unique tau pathology. However, multiple neuropathological features have been reported for DP/CTE beyond tau pathologies, including brain atrophy, amyloid-? plaques, TDP-43 pathologies and neuroinflammation. Furthermore, it is now recognized that almost all of these pathologies are observed in a proportion of cases years after just one moderate to severe single TBI (sTBI). As TBI-associated neurodegeneration has become a major health concern, there is a clear and pressing need to develop robust operational neuropathological criteria for diagnosis, which will, in turn, be critical to the success of all fuure mechanistic, diagnostic and interventional studies. Towards this end, we have assembled an international, multidisciplinary team of experts who provide unparalleled experience in both the study of long-term neurodegeneration after TBI, and the development of optimized assessment of common neuropathological diseases including Alzheimer's disease (AD). Through our team members, we have custodial access to the only comprehensive TBI brain archives in the US and UK that include both sTBI and rTBI cases as well as ~1500 longitudinally followed and extensively characterized autopsy confirmed cases of AD and related disorders for comparison. For our primary Aim 1, we will use a standardized approach successfully applied to AD, to generate baseline diagnostic neuropathological criteria using existing post-mortem material of sTBI and rTBI. In Aim 2 we will pursue biochemical, and genetic studies to explore potential associations with neuropathological outcomes from chronic TBI. In Aim 3 we will explore the temporal course of neuroinflammation to examine its potential role in progressive neurodegeneration following TBI. Finally, in Aim 4 will secure a networked archive of the extensive resources of data and biospecimens generated in Aims 1-3 for wider access across the research community.